The objectives of the research program are to characterize the relationship between histone metabolism and growth rate in normal and neoplastic tissues, and to determine the potential of exogenous histones to serve as inhibitors of the growth of cancer tissues. Experiments will be performed primarily with transplanted Morris hepatomas, normal liver and regenerating liver of the rat. Additional studies will be done with L1210 cells maintained in mice. The nature of DNA-histone binding will be examined as a guide to changes in chromosomal structure which may be related to cell division. The influence of drugs which inhibit DNA synthesis will be investigated to provide information on the degree of coupling of DNA replication with alterations in histone metabolism. Agents to be investigated include thiaxanthenones related to Miracil D, cyanate and hydroxyurea and its structural analogues. The specificity of drug action will be studied with nuclear populations isolated according to size on sucrose gradients. The influence of host age on tumor growth and response to inhibitors of DNA synthesis will be examined. Comparisons will be made between the action of X-irradiation and drugs acting on DNA synthesis. Studies on the effects of exogenous histones on neoplastic cells will be directed particularly to the action of those histones whose concentration has been noted to change in hepatomas, namely the fla and phosphorylated fl histones. This work will require the isolation of histone fractions from tissues of different growth rates. In examining the action of histone fractions on cellular proliferation, attention will be directed to possible synergistic effects of histones and anti-metabolites acting on DNA synthesis.